Dyskeratosis congenita, autosomal recessive 5

Summary

Dyskeratosis congenita, autosomal recessive 5 (MONDO:0014076) is a disease caused by RTEL1 (GenCC Definitive), with 7 cohort genes.

At a glance

• Causal gene: RTEL1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 3,478

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, autosomal recessive 5
Mondo ID	MONDO:0014076
OMIM	615190
DOID	DOID:0070022
NCIT	C176928
UMLS	C3554656
MedGen	767570
GARD	0015917
Is cancer (heuristic)	no

Also known as: DKCB5 · dyskeratosis congenita, autosomal recessive 5 · dyskeratosis congenita, autosomal recessive type 5

Data availability: 3,478 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › dyskeratosis congenita, autosomal recessive 5

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

387 likely benign, 150 uncertain significance, 17 pathogenic, 16 benign, 13 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068424	NM_001283009.2(RTEL1):c.1236_1266+47del	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069534	NM_001283009.2(RTEL1):c.1603G>T (p.Glu535Ter)	RTEL1	Pathogenic	criteria provided, single submitter
1069734	NM_001283009.2(RTEL1):c.2098del (p.Arg700fs)	RTEL1	Pathogenic	criteria provided, single submitter
1070371	NM_001283009.2(RTEL1):c.3043C>T (p.Gln1015Ter)	RTEL1	Pathogenic	criteria provided, single submitter
1071073	NM_001283009.2(RTEL1):c.1458del (p.Ser487fs)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071517	NC_000020.10:g.(?62290746)(62290867_?)del	RTEL1	Pathogenic	criteria provided, single submitter
1071518	NC_000020.10:g.(?62298812)(62298916_?)del	RTEL1	Pathogenic	criteria provided, single submitter
1071780	NM_001283009.2(RTEL1):c.2653G>T (p.Glu885Ter)	RTEL1	Pathogenic	criteria provided, single submitter
1071913	NM_001283009.2(RTEL1):c.3766C>T (p.Gln1256Ter)	RTEL1	Pathogenic	criteria provided, single submitter
1072324	NM_001283009.2(RTEL1):c.329_332del (p.Ile110fs)	RTEL1	Pathogenic	criteria provided, single submitter
1072371	NM_001283009.2(RTEL1):c.3074_3096del (p.Gly1025fs)	RTEL1	Pathogenic	criteria provided, single submitter
1073438	NC_000020.10:g.(?62290746)(62312082_?)del	RTEL1	Pathogenic	criteria provided, single submitter
1075174	NM_001283009.2(RTEL1):c.3553del (p.Arg1186fs)	RTEL1	Pathogenic	criteria provided, single submitter
1076662	NM_001283009.2(RTEL1):c.3138del (p.Ser1047fs)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076689	NM_001283009.2(RTEL1):c.2554C>T (p.Gln852Ter)	RTEL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076873	NM_001283009.2(RTEL1):c.1194del (p.Ile398fs)	RTEL1	Pathogenic	criteria provided, single submitter
1325019	NM_001283009.2(RTEL1):c.2821G>T (p.Glu941Ter)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342130	NM_001283009.2(RTEL1):c.3109+1G>C	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358040	NM_001283009.2(RTEL1):c.1890dup (p.Leu631fs)	RTEL1	Pathogenic	criteria provided, single submitter
1361216	NC_000020.10:g.(?62298812)(62303984_?)del	RTEL1	Pathogenic	criteria provided, single submitter
1364279	NM_001283009.2(RTEL1):c.2584_2593del (p.Leu862fs)	RTEL1	Pathogenic	criteria provided, single submitter
1338484	NM_001283009.2(RTEL1):c.190C>T (p.Arg64Ter)	RTEL1-TNFRSF6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350840	NM_001283009.2(RTEL1):c.46C>T (p.Gln16Ter)	RTEL1-TNFRSF6B	Pathogenic	criteria provided, single submitter
1066098	NC_000020.10:g.(?62292641)(62327221_?)del	RTEL1	Likely pathogenic	criteria provided, single submitter
1066573	NM_001283009.2(RTEL1):c.1191+1G>A	RTEL1	Likely pathogenic	criteria provided, single submitter
1066646	NM_001283009.2(RTEL1):c.3343+1G>C	RTEL1	Likely pathogenic	criteria provided, single submitter
1066945	NM_001283009.2(RTEL1):c.1266+2T>G	RTEL1	Likely pathogenic	criteria provided, single submitter
1067185	NM_001283009.2(RTEL1):c.2265+1G>T	RTEL1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068395	NM_001283009.2(RTEL1):c.3787del (p.Gln1263fs)	RTEL1-TNFRSF6B	Likely pathogenic	criteria provided, single submitter
1025410	NM_001283009.2(RTEL1):c.2483G>A (p.Arg828Gln)	RTEL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RTEL1	Definitive	Autosomal recessive	dyskeratosis congenita, autosomal recessive 5	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy
EEF1A2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
EEF1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	gencc,clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
TNFRSF6B	HGNC:11921	ENSG00000243509	O95407	Tumor necrosis factor receptor superfamily member 6B	clinvar
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	clinvar
RTEL1-TNFRSF6B	HGNC:44095	ENSG00000026036		RTEL1-TNFRSF6B readthrough (NMD candidate)	clinvar
ARFRP1	HGNC:662	ENSG00000101246	Q13795	ADP-ribosylation factor-related protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TNFRSF6B	Tumor necrosis factor receptor superfamily member 6B	Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL.
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
ARFRP1	ADP-ribosylation factor-related protein 1	Trans-Golgi-associated GTPase that regulates protein sorting.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	7	1.8×	0.017

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TNFRSF6B	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFRSF6B_N, TNFRSF_decoy_receptor
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
RTEL1-TNFRSF6B	Other/Unknown	no
ARFRP1	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
olfactory bulb	2
type B pancreatic cell	2
apex of heart	2
sural nerve	1
stromal cell of endometrium	1
olfactory segment of nasal mucosa	1
spleen	1
subcutaneous adipose tissue	1
cingulate cortex	1
cortical plate	1
right lobe of liver	1
gastrocnemius	1
hindlimb stylopod muscle	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TNFRSF6B	127	broad	yes	olfactory segment of nasal mucosa, spleen, subcutaneous adipose tissue
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle
RTEL1-TNFRSF6B	135		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum
ARFRP1	289	ubiquitous	marker	type B pancreatic cell, apex of heart, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
RTEL1	2,324
CHRNA4	1,989
ARFRP1	1,493
EEF1A2	745
TNFRSF6B	650
RTEL1-TNFRSF6B	0

Intra-cohort edges

A	B	Sources
RTEL1	TERT	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
CHRNA4	P43681	12
TNFRSF6B	O95407	8
RTEL1	Q9NZ71	3
EEF1A2	Q05639	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARFRP1	Q13795	90.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 7 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Extension of Telomeres	2	200.3×	0.001	RTEL1, TERT
Telomere Extension By Telomerase	2	152.3×	0.001	RTEL1, TERT
Telomere Maintenance	2	122.8×	0.001	RTEL1, TERT
Chromosome Maintenance	2	70.5×	0.003	RTEL1, TERT
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	271.9×	0.023	CHRNA4
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	271.9×	0.023	TERT
Highly calcium permeable nicotinic acetylcholine receptors	1	211.5×	0.024	CHRNA4
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	173.0×	0.024	CHRNA4
Presynaptic nicotinic acetylcholine receptors	1	158.6×	0.024	CHRNA4
Acetylcholine binding and downstream events	1	135.9×	0.024	CHRNA4
Postsynaptic nicotinic acetylcholine receptors	1	135.9×	0.024	CHRNA4
Cytosolic iron-sulfur cluster assembly	1	126.9×	0.024	RTEL1
Resolution of D-Loop Structures	1	105.7×	0.027	RTEL1
Cell Cycle	2	12.0×	0.028	RTEL1, TERT
TNFs bind their physiological receptors	1	65.6×	0.035	TNFRSF6B
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	65.6×	0.035	RTEL1
Homology Directed Repair	1	51.4×	0.040	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	51.4×	0.040	RTEL1
Eukaryotic Translation Elongation	1	46.4×	0.042	EEF1A2
DNA Double-Strand Break Repair	1	41.4×	0.044	RTEL1
Retrograde transport at the Trans-Golgi-Network	1	36.6×	0.048	ARFRP1
HDR through Homologous Recombination (HRR)	1	31.7×	0.052	RTEL1
MITF-M-dependent gene expression	1	30.2×	0.053	TERT
Formation of the beta-catenin:TCF transactivating complex	1	20.0×	0.072	TERT
TCF dependent signaling in response to WNT	1	19.6×	0.072	TERT
MITF-M-regulated melanocyte development	1	19.0×	0.072	TERT
Signaling by WNT	1	18.7×	0.072	TERT
Intra-Golgi and retrograde Golgi-to-ER traffic	1	17.5×	0.073	ARFRP1
Neurotransmitter receptors and postsynaptic signal transmission	1	16.7×	0.073	CHRNA4
DNA Repair	1	16.4×	0.073	RTEL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA strand displacement	1	2808.7×	0.003	RTEL1
RNA-templated transcription	1	2808.7×	0.003	TERT
DNA strand elongation	1	2808.7×	0.003	TERT
positive regulation of lipid kinase activity	1	2808.7×	0.003	EEF1A2
siRNA transcription	1	2808.7×	0.003	TERT
positive regulation of transdifferentiation	1	2808.7×	0.003	TERT
negative regulation of telomere maintenance in response to DNA damage	1	2808.7×	0.003	RTEL1
positive regulation of telomeric loop disassembly	1	2808.7×	0.003	RTEL1
telomere maintenance	2	89.2×	0.003	RTEL1, TERT
RNA-templated DNA biosynthetic process	1	1404.3×	0.005	TERT
positive regulation of hair cycle	1	1404.3×	0.005	TERT
telomeric loop disassembly	1	1404.3×	0.005	RTEL1
mitotic telomere maintenance via semi-conservative replication	1	936.2×	0.006	RTEL1
negative regulation of t-circle formation	1	936.2×	0.006	RTEL1
positive regulation of telomere capping	1	561.7×	0.009	RTEL1
regulation of chaperone-mediated autophagy	1	561.7×	0.009	EEF1A2
positive regulation of telomere maintenance via telomere lengthening	1	468.1×	0.009	RTEL1
positive regulation of protein localization to nucleolus	1	468.1×	0.009	TERT
establishment of protein localization to telomere	1	351.1×	0.012	TERT
siRNA processing	1	312.1×	0.012	TERT
behavioral response to nicotine	1	312.1×	0.012	CHRNA4
telomere maintenance in response to DNA damage	1	312.1×	0.012	RTEL1
inhibitory postsynaptic potential	1	280.9×	0.012	CHRNA4
DNA repair	2	21.3×	0.012	RTEL1, CHRNA4
telomere maintenance via recombination	1	255.3×	0.013	TERT
translational elongation	1	200.6×	0.014	EEF1A2
regulation of dopamine secretion	1	200.6×	0.014	CHRNA4
nervous system process	1	200.6×	0.014	CHRNA4
negative regulation of DNA recombination	1	187.2×	0.015	RTEL1
regulation of double-strand break repair via homologous recombination	1	165.2×	0.015	RTEL1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TERT	BERBERINE
CHRNA4	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA4	64	4
TERT	10	4
RTEL1	0	0
TNFRSF6B	0	0
EEF1A2	0	0
RTEL1-TNFRSF6B	0	0
ARFRP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
VARENICLINE	4	CHRNA4
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
TERT	391	Binding:389, Functional:2
EEF1A2	8	Binding:8

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TERT	391
CHRNA4	624

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
VARENICLINE	4	CHRNA4
PONATINIB	4	CHRNA4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4
ILOPERIDONE	4	CHRNA4
MOXISYLYTE	4	CHRNA4
RIFAXIMIN	4	CHRNA4
DAUNORUBICIN	4	CHRNA4
PALBOCICLIB	4	CHRNA4
OXYPERTINE	4	CHRNA4
VANDETANIB	4	CHRNA4
MEDAZEPAM	4	CHRNA4
RIFAMPIN	4	CHRNA4
ZIMELDINE	4	CHRNA4
THIORIDAZINE	4	CHRNA4
SUNITINIB	4	CHRNA4
EPALRESTAT	4	CHRNA4
NIMESULIDE	4	CHRNA4
TROPISETRON	4	CHRNA4
FENTANYL	4	CHRNA4
CRIZOTINIB	4	CHRNA4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TERT, CHRNA4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	RTEL1, TNFRSF6B, EEF1A2, RTEL1-TNFRSF6B, ARFRP1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RTEL1	0	—
TNFRSF6B	0	—
EEF1A2	8	—
RTEL1-TNFRSF6B	0	—
ARFRP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.